Synthesis of Novel Selenium Containing Sulfa Drugs and Their Antibacterial Activities

Article abstract of DOI:10.1134/S1068162010030131

Synthesis of 3-[4-(N-substituted sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9- dimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidines,7-[4-(N-substituted sulfamoyl)phenyl]-7,8-dihydro-8-oxo-3,4-diphenylpyrimido[4',5':4,5]selenolo [2,3-c]pyridazines and 1-[4-(N-su

Full text of DOI:10.1134/S1068162010030131

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2010, Vol. 36, No. 3, pp. 370–376. © Pleiades Publishing, Ltd., 2010.
Synthesis of Novel Selenium Containing Sulfa Drugs
and Their Antibacterial Activities1
Sh. H. AbdelꢀHafez
Chemistry department, Faculty of Science, Assiut University, Assiut 71516, Egypt
eꢀmail: shams@aun.edu.eg, sabdel68@yahoo.co.uk
Received November 10, 2009; in final form, December 9, 2009
Abstract
do[3',2':4,5]selenolo[3,2ꢀ
diphenylpyrimido[4',5':4,5]selenolo [2,3ꢀ
hydro 11ꢀoxoꢀ4ꢀmethylpyrimido[4',5':4,5]selenolo[2,3ꢀ
benzene sulfonamide (a), 4ꢀaminoꢀ ꢀ(2,6ꢀdimethylpyrimidinꢀ4ꢀyl)benzene sulfonamide (b),
nophenyl)sulfonyl] acetamide (c) with ꢀethoxymethyleneamino of selenolo pyridine, selenolo pyridazine and
selenolo quinoline derivatives respectively were obtained starting from 1ꢀaminoꢀN4
substituted sulfanilamides.
Spectroscopic data (IR, 1H NMR, 13C NMR and Mass spectral) confirmed the structure of the newly syntheꢀ
sized compounds. Substituted pyrimidines pyridazines and quinolines were screened for antibacterial activity
against gramꢀpositive and gramꢀnegative bacteria. Selenolo derivative of ꢀ[(4ꢀaminophenyl)sulfonyl] acetaꢀ
mide (substitutent of sulfacetamide c) showed strong bactericidal effect against all the tested organisms. Selenoꢀ
lo[3,2ꢀ ]pyrimidin (substitutent a) showed a good bactericidal effect against Serratia marcescens, Staphylococꢀ
cus aureus and Escherichia coli. Compounds selenolo[2,3ꢀ ]pyridazine (substitutent b), selenolo[2,3ꢀ ]quinoꢀ
line(substitutents c)) exhibited a moderate bactericidal effect against Serratia marcescens. None of the
synthesized seleno pyridazines has a considerable antimicrobial activity against the tested organisms. The minꢀ
imum inhibitory concentration (MIC) of the most active compound—3 [4ꢀ( ꢀacetyl sulfamoyl)phenyl]ꢀ3,4ꢀ
dihydroꢀ4ꢀoxoꢀ7,9ꢀdimethylpyrido[3',2':4,5]selenolo [3,2ꢀ
]pyrimidine was 10 mg ml–1.
—
Synthesis of 3ꢀ[4ꢀ(
pyrimidines,7ꢀ[4ꢀ(
pyridazines and 1ꢀ[4ꢀ(
quinolines is reported. 4ꢀAminoꢀ
N
ꢀ
substituted sulfamoyl)phenyl]ꢀ3,4ꢀdihydroꢀ4ꢀoxoꢀ7,9ꢀdimethylpyriꢀ
substituted sulfamoyl)phenyl]ꢀ7,8ꢀdihydroꢀ8ꢀoxoꢀ3,4ꢀ
substituted sulfamoyl)phenyl]ꢀ1,11ꢀdiꢀ
ꢀpyrimidineꢀ2ꢀylꢀ
ꢀ[(4ꢀamiꢀ
d]
Nꢀ
c
]
Nꢀ
b]
N
N
N
N
ꢀ
,
N
d
c
b
ꢀ
N
d
Key words: sulfa drugs, selenolo pyridine, selenolo pyridazine, selenolo quinoline, antibacterial activity
DOI: 10.1134/S1068162010030131
1
INTRODUCTION
pounds may increase the biological activities and act as
antiinflammatory, analgesic, fungicidal and bacteriꢀ
cidal. Considering the foregoing benefits, we aimed to
link biologically active sulfonamides (e.g. Sulfadiazꢀ
ine, Sulfadimidine and Sulfacetamide) with organo
selenium derivatives to access new classes of biologiꢀ
cally active compounds.
Our laboratory has a long standing in the chemistry
of selenium containing heterocycles with discovery
and development of the synthesis of new heterocyclic
systems to search for biological active compounds
[1–4]. Recently, the explosive growth of the interest in
organoselenium chemistry can be attributed to the
specific properties and pharmaceutical applications
[5–10]. On the other hand sulfonamide drugs (known
widely as “sulfa drugs”) were the first antimicrobial
drugs, and paved the way for the antibiotic revolution
in medicine. Moreover, sulfonamides have a variety of
biological activities such as antibacterial [11], insulin
releasing [12], antiꢀinflammatory [13] and antiꢀtumor
activities [14]. Previous work in our laboratory
CHEMISTRY
In order to obtain compounds containing seleꢀ
nium in their structures, nitrile compounds (2),
(
6
)
or (
compounds are readily obtained by previously
described procedures [1–4]. The synthetic method
for compounds (4a)–(4c 7a)–(7c) and (10a)–
10c) is modification of hitherto known procedure
[15, 16]. Upon treatment of ꢀethoxymethyleneꢀ
aminoselenolo pyridine ( ), selenolo pyridazine
) or selenolo quinoline ( ) derivatives with
1ꢀaminoꢀ
4ꢀsubstituted sulfanilamides (3a)–(3c) to
give 3ꢀ[4ꢀ( ꢀsubstituted sulfamoyl)phenyl]ꢀ3,4ꢀ
dihydroꢀ4ꢀoxoꢀ7,9ꢀdimethylpyrido[3',2':4,5]seleꢀ
nolo [3,2ꢀ ] pyrimidine (4a)–(4c) (Scheme 1), 7ꢀ
[4ꢀ( ꢀsubstituted sulfamoyl)phenyl]ꢀ7,8ꢀdihyꢀ
9) were used as the precursors, since these
), (
describes the synthesis of selenolo[2,3ꢀ
b]pyridine, seleꢀ
nolo[2,3ꢀ ]pyridazine, selenolo [2,3ꢀ ]quinoline derivꢀ
(
c
b
N
atives, which indicate that certain compounds bearing
the selenophene with pyridine, pyridazine and quinoꢀ
line nucleus possess significant antiꢀinflammatory and
analgesic activities with strong fungicidal effects [1–
4]. For this reason the synthetic connection of sulfa
drugs with selenium containing heterocyclic comꢀ
2
(
6
9
N
N
d
1
The article is published in the original.
N
370

SYNTHESIS OF NOVEL SELENIUM CONTAINING SULFA DRUGS
371
droꢀ8ꢀoxoꢀ3,4ꢀdiphenyl pyrimido [4',5':4, 5]seleꢀ (Scheme 3). It is worthy to mention that these
nolo[2,3ꢀ ]pyridazine (7a)–(7c) (Scheme 2) and products (4a)–(4c), (7a)–(7c) and (10a)–(10c
1ꢀ[4ꢀ( ꢀsubstituted sulfamoyl)phenyl]ꢀ1,11ꢀ were obtained via oxidation of imino group in pyriꢀ
dihydroꢀ11ꢀoxoꢀ4ꢀmethylpyrimido[4',5':4,5]seleꢀ midine ring into ketone under reaction condition
nolo [2,3ꢀ ]quinoline (10a)–(10c) respectively in acidic medium.
c
)
N
b
Me
Me
N
NH2
CN
N
CHOEt
CN
O
a
+
H2N
S NHR
O
Se
Se
Me
N
Me
O
(
1
)
(
2
)
(
3a–c)
b
Me
O
N
Me
+
N
N
S NHR
H
N
S NHR
O
O
NH
Se
Me
N
O
Se
Me
N
(
4a–c)
N
Where (3a, 4a): R =
N
N
CH3
CH3
(
3b, 4b): R =
N
O
(3c, 4c): R =
CH3
Scheme 1.
a
= Triethylortho formate/Ac O;
b
= gl. acetic acid.
2
Ph
Ph
NH2
CN
N
CHOEt
O
Ph
Ph
a
+
H2N
S NHR
O
CN
N
N
Se
Se
N
N
(
5)
(6)
(3a–c)
b
Ph
O
Ph
N
O
N
N
+
Ph
N
S NHR
H
Ph
N
O
S NHR
O
O
N
N
NH
Se
Se
N
(
7a–c)
N
Where (3a, 7a): R =
N
N
CH3
CH3
(
3b, 7b): R =
3c, 7c): R =
N
O
(
CH3
Scheme 2. a = Triethylortho formate/Ac O; b = gl. acetic acid.
2
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 36
No. 3
2010

372
ABDELꢀHAFEZ
Me
Me
N
NH2
CN
N
CHOEt
O
a
+
H2N
S NHR
O
CN
Se
Se
N
(8
)
(9)
(3a–c)
b
O
Me
N
N
O
Me
N
N
+
N
S NHR
H
N
S NHR
O
O
NH
Se
O
Se
(10a–c)
N
Where (3a, 10a): R =
N
N
CH3
CH3
(
3b, 10b): R =
3c, 10c): R =
N
O
(
CH3
Scheme 3. a = Triethylortho formate/Ac O; b = gl. acetic acid.
2
13
IR spectra of the nitrile compounds (2), (6) and (9)
ment with the proposed structures. In C NMR specꢀ
exhibited characteristic bands at 2200 cm–1 (CN), 1645– trum of compound (4b) sixteen peaks were observed. The
1640 cm–1 (>C=N) and disappearance of peaks at 3250–
3350 cm–1 of amino group (NH2) of starting compounds
sulfonamide and carbonyl carbons of pyrimidine ring are
resonated at 219.59 ppm and 167.41 ppm respectively.
The aromatic carbon atoms in addition carbon atom of
dimidine resonate at 119.99–147.91 ppm. The 13C NMR
(
1
), (
) and (9
5
) and (
8 2),
). In 1HꢀNMR spectra of compounds (
(6
) displayed a quartet and triplet like signals at
spectrum of compound (9) twelve peaks were observed.
4.5–3.5 (for CH2) and 1.5–1.2 ppm (for CH3) correꢀ
sponding to the protons of ethoxy group (OCH2CH3)
and disappearance of signals corresponding to the proꢀ
tons of amino group. The structures of the final products
The most important Peaks at 219.58 ppm is due to
N=CHO, 125.46–132.63 ppm—to quinoline ring carꢀ
bon atoms, 69.11 ppm CH2—to ethoxy carbon atom and
14.32 ppm CH3—to quinoline ring.
(
4a)–(4c), (7a)–(7c) and (10a)–(10c) have been eluciꢀ
1
dated based on their elemental analysis, IR, HꢀNMR
and 13C NMR. All spectral data were in accordance with
the assumed structures. In IR spectra, of compounds
BIOLOGICAL SCREENING
Five bacterial test organisms such as Serratia marceꢀ
scens (bꢀ55), Escherichia coli (bꢀ53) and Pseudomonas
aeruginosa (bꢀ73), Bacillus cereus (bꢀ52) and Staphyloꢀ
coccus aureus (bꢀ54) were obtained from Assiut Universiꢀ
ty Mycological Center. The tested organisms were mainꢀ
tained on nutrient agar slants and were sub cultured in
Petri dishes prior to testing. The media used was nutrient
agar. The Minimum inhibitory concentration (MIC) was
determined by the test tube dilution technique using Sulꢀ
fadiazine, Sulfadimidine and Sulfacetamide as standard
drugs.
(
4a)–(4c), (7a)–(7c) and (10a)–(10c) appeared a charꢀ
acteristic bands at 3300, 3310, 3320 cm–1 confirmed the
presence of (NꢀH stretching) of sulfonamides fused toꢀ
gether with selenium compounds, also, the appearance
of significant bands at 1705, 1700 cm–1 due to ring cloꢀ
sure of pyrimidine ring and confirmed the oxidation of
1
imino group into carbonyl group (C=O). In HꢀNMR
spectra, all protons were seen according to the expected
chemical shifts and integral values. The most important
protons of compounds (4a
10c) are appearance signals at 8.6–9.0 ppm due to ring
closure (CHꢀpyrimidine).
)–(4c), (7a)–(7c) and (10a)–
(
RESULTS AND DISCUSSION
Further confirmation of the structure was through 13C
NMR spectra for compounds ( ) and final product (4b
only and this due to slightly solubility of the final comꢀ
pounds. The signals obtained were all in a good agreeꢀ for their antibacterial activity against gramꢀpositive
9
)
All the newly synthesized compounds (4a)–(4c),
7a)–(7c) and (10a)–(10c) were screened in vitro
(
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 36
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2010

SYNTHESIS OF NOVEL SELENIUM CONTAINING SULFA DRUGS
373
Antibacterial activity of compounds (4a)–(4c), (7a)–(7c) and (10a)–(10c
)
Inhibition zone (mm) for compounds
Organism
(
4a)
(
4b)
(4c)
(
7a)
(7b)
(7c)
(10a) (10b) (10c) Ref* Ref** Ref***
S. marcescens (ꢀve) AUMC bꢀ55
B. cereus (+ve) AUMC bꢀ52
S. aureus (+ve) AUMC bꢀ54
E. coli (ꢀve) AUMC bꢀ53
12
0
10
0
14
11
18
14
12
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
10
0
10
0
10
0
24
20
0
22
14
0
20
14
0
14
12
0
0
0
0
0
0
0
0
0
18
0
16
0
14
0
P. aeruginosa (ꢀve) AUMC bꢀ73
0
0
0
0
Minimum inhibitory concentration (mg mlꢀ1) for compounds
Organisms
(4a)
(
4b 4c 10a) (10b) (10c Ref* Ref**
)
(
)
(
)
Ref***
100 50 100 100 50 100 100 100 100 50 100 50 100 50
S. marcescens (ꢀve) AUMC bꢀ55
B. cereus (+ve) AUMC bꢀ52
S. aureus (+ve) AUMC bꢀ54
E. coli (ꢀve) AUMC bꢀ53
10
0
0
0
0
0
0
0
0
0
0
0
12
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
24 22 22 22 16 16
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
10
0
14
0
P. aeruginosa (ꢀve) AUMC bꢀ73
0
0
Slightly sensitive (inhibition zone 5–10), fairly sensitive (inhibition zone 11–15), highly sensitive (inhibition zone 16–20), very highly
sensitive 21–25).
* Ref = Sulfadiazine, ** Ref = Sulfadimidine, *** Ref = Sulfacetamide.
Amount added from each sample = 50 μl/ pore.
AUMC = Assiut University Mycological Center.
(
B. cereus and S. aureus) and gramꢀnegative (S. marceꢀ scens, P. aeruginosa and B. cereus respectively and have
abroad spectrum than standard drugs. Therefore, it
can be inferred that presence of donor substitute acetyl
group in sulfacetamide imparts much towards antibacꢀ
terial power of these compounds in addition to the
presence of pyridine nucleus bearing the selenophene.
The data also revealed that the activity of compounds
diminished such as (4c) > (4a) > (4b) > (10a)–(10c) >
scens, E. coli and P. aeruginosa) bacteria. Compound (4c
)
showed strong significant activity against all species of
gramꢀpositive and gramꢀnegative bacteria (inhibition
zone 14, 11, 18, 14, 12 mm respectively as in Table). We
can attributed this to the presence of acetyl group in sulꢀ
facetamide. Replacing acetyl group with pirimidineꢀ2ꢀyl)
moiety in compound (4a) resulted in lower activity than
compound (4c) (inhibition zone 12 mm against
S. marcescens, 14 mm against S. aureus and 12 mm
against E. coli). Replacing pirimidineꢀ2ꢀyl) moiety with
4,6ꢀdimethylpyrimidineꢀ2ꢀyl moiety (4b) showed lower
activity compared to (4c) and (4a) against gramꢀnegative
(
7a)–(7c) and this means the fusion of different hetꢀ
erocyclic rings (pyridine, pyridazine and quinoline)
and selenophene moiety exert a significance influence
on the antibacterial activity. The presence of pyridine
ring showed greater activity than that of quinoline and
pyridazine. The most active compound was (4c) which
contains a selenolo pyridine ring. This indicates that
the presence of pyridine moiety in addition the presꢀ
ence of acetyl group in sulfa drug as mentioned before
is additive towards antibacterial activity in this class of
compounds.
bacteria S. marcescens with inhibition zone 10 mm
.
Compounds (10a), (10b) and (10c) showed slightly senꢀ
sitive against gramꢀnegative bacteria S. marcescens
(inhibition zone 10 mm). Compounds (7a), (7b) and
(
7c) were inactive against all gramꢀpositive and gramꢀ
negative bacteria. The minimum inhibitory concentraꢀ
tion (MIC) of the most active compound (4c) which
contain sulfacetamide group bearing with selenolo pyriꢀ
dine was 10 mg ml–1 with inhibition zone 14 mm against
S. aureus bacteria and 12 mm against S. marcescens as
shown in Table.
EXPERIMENTAL
Melting points were determined using a Kofler meltꢀ
ing point apparatus (C. Reichert, Vienna, Austria) and
are uncorrected. IR (KBr) spectra were recorded on a
PyeꢀUnicam SP3ꢀ100 instrument (Pye Unicam Ltd.
Cambridge, England). H NMR spectra were obtained
on a Varian EM 390 (Varian Inc., Palo Alto, CA, USA)
using tetramethylsilane as an internal reference. Mass
In general, compounds (4b), (10a), (10b) and
1
(
10c) were moderate potent against S. marcescens as
compared to the standard drugs (Sulfadiazine, Sulfadiꢀ
midine and Sulfacetamide) while, compound (4c) was
found more potent against S. aureus, E. coli, S. marceꢀ spectra were recorded on a JEOLꢀJMSꢀAX 600
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 36
No. 3
2010

374
ABDELꢀHAFEZ
(JEOL, Tokyo, Japan) at Assiut University, Assiut, Egypt. moyl)phenyl]ꢀ1,11ꢀdihydroꢀ11ꢀoxoꢀ4ꢀmethylpyrimiꢀ
M+ ions are given for 80Se unless otherwise stated; the
mass spectra were recorded via FAB inlet. 13C NMR
spectra were recorded on a GEMINIꢀ200 ‘‘NMR200’’
at Cairo University. Elemental analyses were obtained on
an Elementar Vario EL 1150C analyzer (Heraeus, Gerꢀ
many). The purity of the compounds was checked by
TLC. Sulfonamides derivatives were obtained from Aldꢀ
rich and used without further purification.
do[4',5':4,5]selenolo[2,3ꢀb]quinolines (10a)–(10c).
General Procedures
The iminoethers ( ), ( ) or ( ) (10 mmol) were heatꢀ
2
6
9
ed under reflux with compounds (3a)–(3c) (10 mmol)
for 4 h in gl. acetic acid. The solid that separated was colꢀ
lected and recrystallized from proper solvent.
Compounds (1), (2), (5) and (8) were prepared as
3ꢀ[4ꢀ(NꢀPyrimidinyl sulfamoyl)phenyl]ꢀ3,4ꢀdihydroꢀ
previously described [1–4].
4ꢀoxoꢀ7,9ꢀdimethylpyrido[3
idine 4a): crystallized from dioxan, mp = 280–282
yield (80%). IR (cmꢀ1) 3300 (NH); 1700 (C=O), 1640
(C=N). 1H NMR (
, ppm) TFA: 9.0 (1 H, s, CHꢀpyriꢀ
midine); 7.8–8.6 (7 H, m, ArꢀH sulfapyridazine, ArꢀH
phenyl); 7.6 (1 H, s, CHꢀpyridine); 3.0 (3 H, s, CH3);
2.2 (3 H, s, CH3), mass spectrum of compound (4a
(C21H16N6O3SSe) exhibited molecular ion peak at
m/z (%) 512 (8) [
+] and the other important fragments
'
,2
':4,5]selenolo[3,2ꢀd]pyrimꢀ
(
°
C,
NꢀEthoxymethyleneamino Derivatives:
Preparation of Compounds ( ), ( ) and (
2
6
9)
δ
,
The nitrile derivatives ( ), ( ) and ( ) (10 mmol) and
1
5
8
triethyl orthoformate (7 ml) were refluxed in acetic anhyꢀ
dride (3 ml) for 5 h. The precipitate that formed on coolꢀ
ing was collected and recrystallized from ethanol as yelꢀ
low crystals.
)
M
were observed at 252 (52), 250 (23), 185 (36), 115 (76),
93 (100). Anal: Calc. for (C21H16N6O3SSe): C, 49.29;
H, 3.15; N, 16.43; S, 6.27. Found: C, 49.92; H, 3.20;
N, 16.06; S, 5.80.
Ethyl Nꢀ(2ꢀcyanoꢀ4, 6ꢀdimethylselenolo[2,3ꢀb]pyriꢀ
dineꢀ3ꢀyl) methanimidate (2).
The resulted data (IR, 1H NMR and MS) see [ref. 2]
Ethyl Nꢀ(6ꢀcyanoꢀ3,4ꢀdiphenylselenolo[2,3ꢀc]pyꢀ
3ꢀ[4ꢀ(Nꢀ2,4ꢀDimethylpyrimidinyl sulfamoyl)phenyl]ꢀ
ridazineꢀ5ꢀyl)methanimidate
ethanol, mp = 178–180
C, yield (86%). IR (cm–1)
2200 (CN); 1645 (C=N). 1H NMR (
, ppm), CDCl3:
7.2–7.4 (10 H, m, ArꢀH); 7.6 (1 H, s, N=CH); 3.5 (2
H, q, CH2); 1.2 (3 H, t, CH3), mass spectrum of comꢀ
pound ( ) (C22H16N4OSe) exhibited molecular ion peak
at m/z (%) 432 (3) [
+] and the other important fragꢀ
(6): crystallized from
3,4ꢀdihydroꢀ4ꢀoxoꢀ7,9ꢀdimethylpyrido[3
[3,2ꢀd]pyrimidine 4b crystallized from dioxan, mp >
300
C, yield (75%). IR (cmꢀ1) 3310 (NH); 1700 (C=O),
1600 (C=N). H NMR (
',2':4,5]selenolo
°
(
):
δ
°
1
δ
, ppm), DMSO: 9.7 (1 H, s,
SO2NH), 8.72 (1 H, s, CHꢀpyrimidine); 6.7–8.70 (5 H,
m, ArꢀH dimidine, ArꢀH phenyl); 7.2 (1 H, s, CHꢀpyriꢀ
dine); 2.8 (3 H, s, CH3); 2.4 (3 H, s, CH3); 2.2 (3 H, s,
6
M
CH3); 1.8 (3 H, s, CH3); 13C NMR (DMSOꢀ
MHz),
d6, 50
219.59 (–SO2NH–C of dimidine), 205.44,
ments were observed at 403 (13), 202 (4), 103 (100).
Anal: Calc. for (C22H16N4OSe): C, 61.24; H, 3.74;
N, 12.99. Found: C, 61.01; H, 3.57; N, 12.75.
δ
167.41 (C=O of pyrimidine ring), 159.66, 156.31,
154.05, 147.91, 143.26, 134.12, 129.52, 128.93, 119.99,
(Aryl), 97.87 (C of dimidine), 23.84, 22.91, 21.02 (CH3
of dimidine and pyridine rings); mass spectrum of comꢀ
pound (4b) (C23H20N6O3SSe) exhibited molecular ion
Ethyl Nꢀ(2ꢀcyanoꢀ4ꢀmethylselenolo[2,3ꢀb]quinolineꢀ
3ꢀyl)methanimidate
150–152
C, yield (76%). IR (cmꢀ1) 2200 (CN); 1640
(C=N). 1H NMR (
, ppm), DMSO: 7.6–8.3 (4 H, m,
(9): crystallized from ethanol, mp =
°
δ
peak at m/z (%) 540 (33) [M M
+ – 1], 541 (5) [ +] and the
ArꢀH); 7.6 (1 H, s, N=CH); 4.4 (2 H, q, CH2); 3.0
(3 H, s, CH3ꢀquinoline); 1.4 (3 H, t, CH3); 13C NMR
other important fragments were observed at 538 (19), 353
(27), 185 (58), 115 (5), 93 (100). Anal: Calc. for
(C23H20N6O3SSe): C, 51.19; H, 3.74; N, 15.58; S, 5.94.
Found: C, 50.98; H, 3.69; N, 15.84; S, 5.79.
(DMSOꢀ
190.07, 132.63, 131.36, 128.30, 125.46 (Aryl), 111.16
(C–CN), 72.65, 69.11 (CH2 and CH3), 14.32 (CH3 of
quinoline), mass spectrum of compound
(C16H13N3OSe) exhibited molecular ion peak at m/z (%)
343 (100) (M+) and the other important fragments were dine
observed at 344 (22) [M+ + 1], 345 (23) [ + + 2], 295 yield (77%). IR (cmꢀ1) 3320 (NH); 1700, 1705 (C=O),
d6, 50 MHz):
δ
219.58 (–N=CH–O), 211.51,
(9)
3ꢀ[4ꢀ(NꢀAcetyl
oxoꢀ7,9ꢀdimethylpyrido[3
4c): crystallized from ethanol, mp = 220–222
sulfamoyl)phenyl]ꢀ3,4ꢀdihydroꢀ4ꢀ
,2 :4,5]selenolo [3,2ꢀd]pyrimiꢀ
C,
'
'
(
°
M
1620 (C=N). 1H NMR (
pyrimidine); 8.3 (4 H, m, ArꢀH phenyl); 7.8 (1 H, s,
CHꢀpyridine); 2.5 (3 H, s, CH3); 2.1 (3 H, s, CH3);
1.7 (3 H, s, CH3), mass spectrum of compound (4c
(C19H16N4O4SSe) exhibited molecular ion peak at m/z
+] and the other important fragments were
selenolo[2,3ꢀ observed at 434 (20), 278 (27), 252 (89), 250 (50), 185
c]pyridazines (7a)–(7c) and 1ꢀ[4ꢀ(Nꢀsubstitutedsulfaꢀ (34), 115 (100), 93 (83). Anal: Calc. for
δ
, ppm), TFA: 8.9 (1 H, s, CHꢀ
(39), 287 (59), 140 (68), 77 (11). Anal: Calc. for
(C16H13N3OSe): C, 56.14; H, 3.83; N, 12.27. Found: C,
56.12; H, 3.64; N, 12.43.
)
3ꢀ[4ꢀ(NꢀSubstituted sulfamoyl)phenyl]ꢀ3,4ꢀdihydroꢀ4ꢀ
oxoꢀ7,9ꢀdimethylpyrido[3
(4a)–(4c), 7ꢀ[4ꢀ(Nꢀsubstituted sulfamoyl)phenyl]ꢀ7,8ꢀdihyꢀ (%) 476 (4) [
droꢀ8ꢀoxoꢀ3,4ꢀdiphenylpyrimido[4 ,5 :4,5]
',2':4,5]selenolo[3,2ꢀd]pyrimidines
M
'
'
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 36
No. 3
2010

SYNTHESIS OF NOVEL SELENIUM CONTAINING SULFA DRUGS
375
1
(C19H16N4O4SSe): C, 47.99; H, 3.39; N, 11.78; S, 6.74.
Found: C, 47.79; H, 3.18; N, 11.47; S, 6.54.
(C=O), 1600 (C=N). H NMR (
δ
, ppm)
,
DMSO: 9.6
(1 H, s, SO2NH); 8.6 (1 H, s, CHꢀdimidine); 7.5–8.0
(4 H, m, ArꢀH phenyl); 6.8 (1 H, s, CHꢀpyrimidine); 3.6
(3 H, s, CH3); 3.2 (3 H, s, CH3); 2.3 (3 H, s, CH3), mass
spectrum of compound (10b) (C26H20N6O3SSe) exhibitꢀ
7ꢀ[4ꢀ(NꢀPyrimidinꢀ2ꢀyl sulfamoyl)phenyl]ꢀ7,8ꢀdihyꢀ
droꢀ8ꢀoxoꢀ3,4ꢀdiphenylpyrimido [4
c]pyridazine 7a): crystallized from ethanol, mp = 202–
204
C, yield (80%). IR (cmꢀ1) 3350 (NH); 1690 (C=O),
1635 (C=N). H NMR (
',5':4,5]selenolo[2,3ꢀ
(
ed molecular ion peak at m/z (%) 576 (1) [
M
+], 574 (2)
°
1
[M
+ – 2] and the other important fragments were obꢀ
δ
, ppm), DMSO: 9.2 (1 H, s,
served at 434 (20), 228 (14), 207 (11), 185 (58), 115 (50),
93 (100). Anal: Calc. for (C26H20N6O3SSe): C, 54.25; H,
3.51; N, 14.60; S, 5.57 Found: C, 54.10; H, 3.34; N,
14.47, S, 5.33.
SO2NH), 8.5 (1 H, s, CHꢀpyrimidine); 7.8–8.5 (17 H, m,
ArꢀH sulfadiazine, ArꢀH phenyl); mass spectrum (EI+) of
compound (7a) (C30H19N7O3SSe) exhibited molecular ion
peak at m/z (%) 403 (44) [M
+ – C10H8N3O2S]. Anal: Calc.
1ꢀ[4ꢀ(NꢀAcetyl sulfamoyl)phenyl]ꢀ1,11ꢀdihydroꢀ11ꢀoxoꢀ
for (C30H19N7O3SSe): C, 56.59; H, 3.01; N, 15.40; S,
5.03. Found: C, 56.38; H, 2.98; N, 15.33; S, 4.98.
4ꢀmethylpyrimido[4
crystallized from dioxan, mp = > 300
(cm–1) 3310 (NH); 1705, 1700 (C=O), 1600 (C=N).
1H NMR (
, ppm), DMSO: 9.6 (1 H, s, SO2NH); 8.9
'
,5
'
:4,5]selenolo[2,3ꢀb]quinoline
(10c):
°C, yield (75%). IR
7ꢀ[4ꢀ(Nꢀ4,6ꢀDimethylpyrimiꢀ2ꢀyl sulfamoyl)phenyl]ꢀ
7,8ꢀdihydroꢀ8ꢀoxoꢀ3,4ꢀdiphenylpyrimido[4
lenolo[2,3ꢀc]pyridazine 7b): crystallized from dioxan,
mp = 220–224
C, yield (77%). IR (cm–1) 3300 (NH);
1700 (C=O), 1640 (C=N). 1H NMR (
, ppm), DMSO:
',5':4,5]seꢀ
δ
(
(1 H, s, CHꢀpyrimidine); 7.3–8.3 (8 H, m, ArꢀH pheꢀ
nyl); 3.2 (3 H, s, CH3); 2.2 (3 H, s, CH3) mass spectrum
of compound (10c) (C22H16N4O4SSe) exhibited molecuꢀ
lar ion peak at m/z (%) 514 (5) [M
+ + 2] and the other imꢀ
portant fragments were observed at 455 (24), 373 (19),
185 (9), 101 (28), 51 (100). Anal: Calc. for
(C22H16N4O4SSe): C, 51.66; H, 3.15; N, 10.95; S, 6.27.
Found: C, 51.44; H, 3.00; N, 10.78; S, 5.98.
°
δ
8.9 (1 H, s, SO2NH), 8.4 (1 H, s, CHꢀpyrimidine); 7.5–
8.0 (15 H, m, ArꢀH phenyl); 2.3 (3 H, s, CH3), 1.8 (3 H,
s, CH3); mass spectrum (EI+) of compound (7b
)
(C32H23N7O3SSe) exhibited molecular ion peak at m/z
(%) 404 (7) [M+ – C12H12N3O2S]. Anal: Calc. for
(C32H23N7O3SSe): C, 57.82; H, 3.49; N, 14.75; S, 4.82.
Found: C, 57.63; H, 3.22; N, 14.54, S, 4.71.
AntiꢀBacterial Assays (in vitro)
7ꢀ[4ꢀ(NꢀAcetyl sulfamoyl)phenyl]ꢀ7,8ꢀdihydroꢀ8ꢀ
oxoꢀ3,4ꢀdiphenylpyrimido[4
ridazine 7c) crystallized from dioxan, mp > 300
(75%). IR (cm–1) 3300 (NH); 1700 (C=O), 1620
(C=N). 1H NMR (
, ppm) TFA: 9.0 (1 H, s, CHꢀpyriꢀ
midine); 7.5–8.3 (14 H, m, ArꢀH phenyl); 1.9 (3 H, s,
CH3), mass spectrum of compound 7c
(C28H19N5O4SSe) exhibited molecular ion peak at m/z
(%) 600 (3) [ M
+ –1], 601 (0.8) [ +] and the other imꢀ sulfadimidine and Sulfacetamide as reference drug by usꢀ
'
,5
'
:4,5]selenolo[2,3ꢀc]pyꢀ
Five bacterial species representing both gramꢀpositive
and gramꢀnegative strains were used to test the antibacteꢀ
(
°C, yield
rial activities of the target compounds (4a)–(4c
), (7a)–
δ
,
(7c) and (10a)–(10c) in vitro against (i) gramꢀnegative
bacteria: S. marcescens (bꢀ55), E. coli (bꢀ53) and (ii)
gramꢀpositive bacteria: P. aeruginosa (bꢀ73), B. cereus
(bꢀ52), S. aureus (bꢀ54) in comparison to sulfadiazine,
(
)
M
portant fragments were observed at 493 (0.3), 297 (1.3), ing the standard agar paper disc diffusion method [17].
277 (3.1), 241 (4.4), 185 (60), 115 (3.7), 93 (100). Anal: Cell suspension of bacterial stains was prepared from 48 h
Calc. for (C28H19N5O4SSe): C, 55.99; H, 3.19; N, 11.66, S, old cultures grown on Potato Dextrose Agar (PDA) or Saꢀ
bouraud Agar (SA) media. One ml of the cell suspension
was added to Petri dishes of 9 cm diameter, and then
15 ml of Nutrient Agar was poured onto the plates. Plates
were shaken gently to homogenize the innoculum. Sulfa
drug (sulfadiazine, sulfadimidine and sulfacetamide) soꢀ
lutions at concentration (100 and 50 mg ml–1) as referꢀ
ence drug. DMSO was used as a solvent control. Impregꢀ
nated discs were then dried for 1 h and placed in the centre
of each plate. The seeded plated were incubated at 35
5.34. Found: C, 55.74; H, 3.00; N, 11.54, S, 5.19.
1ꢀ[4ꢀ(NꢀPyrimidinꢀ2ꢀyl sulfamoyl)phenyl]ꢀ1,11ꢀdihyꢀ
droꢀ11ꢀoxoꢀ4ꢀmethylpyrimido[4
oline 10a): crystallized from dioxan, mp > 300
(80%). IR (cmꢀ1) 3290 (NH); 1700 (C=O), 1640 (C=N).
1H NMR (
, ppm), TFA: 8.5 (1 H, s, CHꢀpyrimidine);
'
,5
'
:4,5]selenolo[2,3ꢀb]quinꢀ
(
°C, yield
δ
7.8–8.6 (11 H, m, ArꢀH); 3.0 (3 H, s, CH3), mass specꢀ
trum of compound (10a) (C24H16N6O3SSe) exhibited
molecular ion peak at m/z (%) 545 (0.2) [M
+ – 3] and the
2°C for 24–48 h. The radii of the inhibition zones in mm
of triplicate sets were measured and the results are given
in Table.
other important fragments were observed at 257 (3),
241(9), 185 (66), 115 (9), 93 (100). Anal: Calc. for
(C24H16N6O3SSe): C, 52.64; H, 2.95; N, 15.35; S, 5.85.
Found: C, 52.35; H, 3.13; N, 15.04; S, 5.45.
ACKNOWLEDGMENTS
1ꢀ[4ꢀ(Nꢀ4,6ꢀDimethylpyrimidinꢀ2ꢀyl sulfamoyl)pheꢀ
nyl]ꢀ1,11ꢀdihydroꢀ11ꢀoxoꢀ4ꢀmethylpyrimido[4
nolo[2,3ꢀb]quinoline 10b): crystallized from dioxan, mp
> 300
',5':4,5]seleꢀ
The author is greatly indebted to the mycological
center at Assiut University for assistance in performing
(
°
C, yield (65%). IR (cm–1) 3295 (NH); 1700 the antiꢀbacterial screening.
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 36
No. 3
2010

376
ABDELꢀHAFEZ
10. Koketsu, M., Tanaka, R., Takenaka, Y., Kwong, C.D.,
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2010